Sequence analysis of mouse H-2 cDNA clones has suggested the existence of a novel class of H-2 (class I) related antigens which, unlike the classical membrane-associated molecules, retains only the extracellular portion and is likely to be secreted. The expression of this class of H-2 related mRNA is tissue restricted; it is detectable in liver, but not in brain, kidney, testis, thymus or spleen. In the liver, its accumulation represents about one-fourth of all the H-2 (class I) specific transcripts. This class of transcripts is present in mice of different inbred strains, but the level of expression differs markedly among them. A model is presented in which such a soluble form of the H-2 antigen would play the role of a blocking factor in maintaining peripheral inhibition of H-2 recognition. This would assure tolerance of the H-2 molecule as a self antigen while permitting it to act as a guidance molecule for the associative recognition of viral and tumor antigens by cytotoxic T cells.